Written by Anushri Sinha

         Imagine being told that a medication might cause a headache or dizziness. Soon after, you start feeling those symptoms, even though the medication hasn’t taken effect. This is the Nocebo Effect, where negative expectations can lead to real physical symptoms. From its historical origins in the 18th century to its modern implications in medicine, the Nocebo Effect reveals how powerful our minds can be in shaping our physical experiences. Understanding its mechanisms and ways to reduce its impact is key to improving patient outcomes.

Historical Perspective

          The roots of the effect trace back to the 18th century. Franz Mesmer, a German physician, proposed the theory of “animal magnetism,” claiming that an invisible magnetic fluid could be manipulated to cure ailments. In a placebo-controlled study, Benjamin Franklin’s team found that patients still experienced side effects like shaking, even without magnets being used (Bernstein et al., 2024).

          In the 20th century, Dr. Harold Diehl discovered the Nocebo Effect while conducting vaccine trials. Some patients given placebos, treatments that have no active properties, reported side effects like headaches and fatigue. Diehl was one of the first to officially observe that negative expectations could cause symptoms even without the presence of an illness-causing substance.

          A decade later, the “June Bug Epidemic” struck a textile factory. Several workers experienced nausea and vomiting, and word spread that invisible bugs in the factory were causing these symptoms. There was a lot of media coverage on the story, and the illness quickly became known as the “June Bug Plague”. Despite thorough investigation, scientists and entomologists never found any bugs or other potential causes for the illness. Psychologists, on the other hand, discovered that out of the 62 workers who fell sick, 50 of them only began having symptoms after viewing information about the sickness from the media. In 2017, the mysterious “Havana Syndrome,” caused U.S. diplomats in Cuba to experience severe neurological symptoms (Bartholomew et al.,  2020). Government physicians believed the illness was caused by a sonic device. After the incident was made public, many American tourists in Cuba and other foreign countries reported similar symptoms. However, there was no evidence of MRI-detectable brain injury. These events raise questions about how collective fear can trigger mass psychogenic illness, potentially linked to the nocebo effect. 

          More recently, studies have shown how media coverage and social contagion can amplify the nocebo effect, influencing public health responses, For example, during the COVID-19 pandemic, individuals who believed they had contracted the virus, despite lacking a positive test result, reported a higher number of symptoms. Further analysis indicated that the certainty of being affected and the anxiety associated with that accounted for 27% of the variance in reported COVID-like symptoms (Daniali et al., 2022).

Mechanisms Behind the Effect

          The nocebo effect starts in the brain, specifically with expectation. When we expect to feel pain or discomfort, the brain can trigger physical reactions that result in these sensations, even in the absence of any underlying cause (Faase & Petrie, 2013). This process is closely tied to the brain’s stress response system, which involves the release of stress hormones such as cortisol, which can cause physical discomfort. The brain can release other chemicals like pro-inflammatory cytokines, which contribute to pain and inflammation. Another factor contributing to the nocebo effect is the brain’s tendency to focus on and amplify negative sensations (Wartolowska, 2019). The expectation of pain or distress alters brain activity, as shown in Figure 2. The brain may become more sensitive to minor physical cues, exaggerating them and making them seem more intense than they truly are (Blasini et al., 2017). 

          The nocebo effect manifests in two ways: primary nocebo effects, where a treatment’s intended effectiveness is reduced, and nocebo side effects, where unpleasant side effects are experienced due to negative expectations (Faasse & Martin, 2018). Recent studies suggest that nocebo effects are so common that up to 97% of reported pharmaceutical side effects are not caused by the drug itself (Faase et al., 2019). This challenges our understanding of treatment outcomes and suggests a need for better communication about treatments, focusing on positive framing.

Figure 1

Nocebo effects are influenced by verbal cues, prior experiences, social observation, and individual psychological traits, leading to physiological changes such as anxiety, activation of the HPA axis and CCK system, and altered brain activity in regions highlighted above.

Source: PAIN Reports

Conclusion

          The Nocebo Effect is a testament to the extraordinary influence our minds have on our bodies. It’s not just about the pills we take, but about how we perceive them. Our thoughts, whether positive or negative, can shape our health in ways we’re only beginning to understand. If expectations can create symptoms, then maybe shifting our mindsets can do the opposite. Replacing negative expectations with a more positive outlook can counteract the tendency to manifest nocebo symptoms. Your brain is always listening, what are you telling it? 

References and Sources

Bartholomew, R. E., & Baloh, R. W. (2020). Challenging the diagnosis of ‘Havana Syndrome’ as a novel clinical entity. Journal of the Royal Society           of Medicine, 113(1), 7–11. https://doi.org/10.1177/0141076819877553.

Bernstein, M. H., Blease, C., Locher, C., & Brown, W. A. (2024). The nocebo effect. Mayo Clinic Press. ISBN 9798887700243. 

Blasini, M., Corsi, N., Klinger, R., & Colloca, L. (2017). Nocebo and pain: An overview of the psychoneurobiological mechanisms. Pain Reports,                     2(2), e585. https://doi.org/10.1097/PR9.0000000000000585.   

Daniali, H., & Flaten, M. A. (2022). Experiencing COVID-19 symptoms without the disease: The role of nocebo in reporting of symptoms.                               Scandinavian journal of public health, 50(1), 61–69. https://doi.org/10.1177/14034948211018385. 

Faasse, K., Helfer, S. G., Barnes, K., Colagiuri, B., & Geers, A. L. (2019). Experimental assessment of nocebo effects and nocebo side effects:                     Definitions, study design, and implications for psychiatry and beyond. Frontiers in Psychiatry, 10, 396.                                                                                                          https://doi.org/10.3389/fpsyt.2019.00396.   

Faasse, K., & Martin, L. R. (2018). The power of labeling in nocebo effects. In L. Colloca (Ed.), International review of neurobiology (Vol. 139, pp. 379–406). Academic Press. https://doi.org/10.1016/bs.irn.2018.07.016. 

Faasse, K., & Petrie, K. J. (2013). The nocebo effect: Patient expectations and medication side effects. Postgraduate Medical Journal, 89(1055),           540–546. https://doi.org/10.1136/postgradmedj-2012-131730. 

Friesen, P. (2019). Mesmer, the placebo effect, and the efficacy paradox: lessons for evidence based medicine and complementary and                               alternative medicine. Critical Public Health, 29(4), 435–447. https://doi.org/10.1080/09581596.2019.1597967.  

Wartolowska, K. (2019). The nocebo effect as a source of bias in the assessment of treatment effects. F1000Research, 8, 5.                                                            https://doi.org/10.12688/f1000research.17611.2.